This invention relates to tetrazole compounds. More particularly, this invention relates to:
(1) tetrazole compounds having interleukin-1xcex2 converting enzyme inhibitory activity of the following formula (I): 
xe2x80x83wherein all of the symbols have the same meanings as described hereinafter, or a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof;
(2) processes for the preparation thereof; and
(3) pharmaceutical agents containing such devivative as an active ingredient.
Interleukin 1 (IL-1) is a key cytokine that directly or indirectly participates in the regulation of, for example, the immune system, hemopoietic system and neuroendocrine system, and thus, has a crucial physiological role. There are two types of IL-1, which have different isoelectric points (IL-1xcex1: pl=5, IL-1xcex2: pl=7). Both of these are produced as a precursor having molecular weight of 31 Kd. The IL-1xcex2 precursor does not bind to the IL receptor nor exerts a biological function. The IL-1xcex2 converting enzyme (ICE) cleaves the precursor protein between Asp 116 and Ala 117 and converts into an active IL-1xcex2 mature form having a molecular weight of 17 Kd. Following the cleavage, IL-1xcex2 is secreted, binds to the receptor and triggers various biological activities (Ref. The New England Journal of Medicine, 328, 106 (1993)).
The inhibition of ICE enzymatic activity leads to prevention of conversion of the IL-1xcex2 precursor into the mature form and hence results in blockage of IL-1 biological activity. There are many possible target diseases for ICE inhibitors, for example, prevention and/or treatment of insulin dependent diabetes (type 1), autoimmune diseases, including multiple sclerosis, immune diseases, such as acute or delayed type hypersensitivity, infectious diseases, infection complications, septic shock, acute or chronic inflammatory diseases, such as arthritis, colitis, glomelular nephritis, hepatitis, pancreatitis, reperfusion injury, cholangeitis, encephalitis, endocarditis, myocarditis and vasculitis, neural diseases, such as Alzheimer""s disease and Parkinson""s disease, bone or cartilage-resorption diseases, Crohn""s disease, osteo arthritis etc.
It is believed that ICE and/or ICE-like cystein proteases play important roles in cell death by apoptosis. Therefore it is possible that an ICE inhibitor may be used in the prevention and/or treatment of diseases resulting from apoptosis disorders, such as infection, reduction or enhancement of immune or central nervous system function, neoplasm etc. Diseases associated with apoptosis disorders are as follows; AIDS, ARC (AIDS related complex), adult T cell leukemia, hairy cell (pilocytic) leukemia, myelosis, respiratory dysfunction, arthropathy, HIV or HTLV-I related diseases, such as uveitis, virus related diseases, such as hepatitis C, neoplasm, diffuse collagen diseases, such as systemic lupus erythematosis or rheumatoid arthritis, autoimmune diseases, such as ulcerative colitis, Sjogren""s syndrome, primary binary cirrhosis, idiopathic thrombocytopnic purpura, autoimmonohaemolytic anemia, severe myasthenia, insulin dependent (type I) diabetes, osteodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, idiopathic thrombocytopenia, various diseases which accompany thrombocytopenia, such as disseminated intravascular coagulation, hepatic diseases, including hepatitis (type C, A, B, or F virus borne or drug mediated) and hepatic cirrhosis, Alzheimer""s disease, dementia, such as Alzheimer type senile dementia, cerebral vascular disturbance, neuro-degenerative diseases, adult dyspnea syndrome, infection, hyperplasia of the prostate, myoma of the uterus, asthma bronchiole, arteriosclerosis, various kinds of congenital teratoma, nephritis, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral nervous disturbance, and so on (Ref. The New England Journal of Medicine, 328, 106-113 (1993), Arthritis and Rheumatism, 39, 1092 (1996)).
Compounds having an inhibitory activity on IL-1xcex2 converting enzyme (ICE) are known. The sequence of the ICE cleavage site of pre-IL-1xcex2 (Tyr-Val-His-Asp) has high affinity with ICE. Substrate analog inhibitors which are chemically modified and based on the above substrate sequence, for example, a compound of formula (X): 
wherein
YX is 
xe2x80x83,or 
R1X is
(a) a substituted C1-12 alkyl (in which a substituent is hydrogen, hydroxy etc.) or
(b) an aryl C1-6 alkyl (in which aryl is phenyl, naphthyl, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, benzoimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, purinyl or isooxazolyl), wherein the aryl can be mono-substituted or di-substituted (in which a substituent is a C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.);
R2X is
(a) hydrogen, 
(in which R3X is
(1) a substituted C1-12 alkyl (in which a substituent is hydrogen, hydroxy etc.), or
(2) an aryl C1-6 alkyl or substituted aryl C1-6 alkyl as hereinbefore defined (in which an aryl may be mono-substituted or di-substituted by C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.);
R4X and R5X are each hydrogen, hydroxyl etc.; and
R6X is
(1) hydrogen,
(2) a substituted C1-6 alkyl (in which a substituent is hydrogen, hydroxyl etc.),
(3) an aryl C1-6 alkyl (in which alkyl is substituted by hydrogen, oxo, C1-3 alkyl etc., aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.),
(4) a C1-6 alkylaminocarbonyl C1-6 alkyl or C1-6 alkylcarbonylamino C1-6 alkyl,
(5) an arylaminocarbonyl C1-6 alkyl or arylcarbonylamino C1-6 alkyl (in which aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.) or
(6) an aryl C1-6 alkylaminocarbonyl C1-6 alkyl or aryl C1-6 alkylcarbonylamino C1-6 alkyl (in which aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.) etc.;
AA1X is a bond etc.;
AA2X is a bond or; and 
AA3X is a bond or 
xe2x80x83(wherein R8X and R9X is
(a) hydrogen,
(b) a substituted C1-6 alkyl (in which a substituent is hydrogen, hydroxyl etc.) or
(c) an aryl C1-6 alkyl (in which aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl, etc.)) (with the proviso that, definitions not related are omitted) are disclosed as having an inhibitory activity on ICE (see EP 519748).
The compounds of formula (Y):
RYxe2x80x94[A1Yxe2x80x94A2Y]nYxe2x80x94A3Yxe2x80x94A4Yxe2x80x94XYxe2x80x94A5Yxe2x80x83xe2x80x83(Y)
wherein
RY is hydrogen, an amino protecting group or benzyloxy, which may be optionally substituted by a ring;
nY is 0 or 1;
A1Y is Val, Leu, Ala, Ile or trimethylsilyl-Ala;
A2Y is Phe or Tyr;
A3Y is Val, Leu, Ala, Ile, trimethylsilyl-Ala or a divalent radical group: 
(in which ring AY may be optionally substituted by hydroxy or C1-4 alkoxy); A4Y is a bond or 
(in which R1Y is hydrogen or C1-4 alkyl, and
Y1Y is a residue bonded to the xcex1-carbon atom of an optionally protected xcex1-amino acid);
wherein
A3Y and A4Y together may form: 
(wherein Y1Y has the same meaning as hereinbefore defined, and R1Y and R1aY are combined to form xe2x80x94(CH2)mYxe2x80x94(in which mY is 2, 3, 4 or 5));
XY is a divalent radical group: 
(wherein R6Y is hydrogen or C1-4 alkyl); and
A5Y is hydrogen, CF3, xe2x80x94Z1Yxe2x80x94Z2Yxe2x80x94Y2Y (in which Z1Y and Z2Y is each, independently, a bond or an xcex1-amino acid residue and Y2Y is NH2, C1-4 alkylamino, di-(C1-4 alkyl)amino or hetero ring bonded to the Z2Y nitrogen), xe2x80x94CH2xe2x80x94X1Yxe2x80x94Y3Y (in which X1Y is O or S and Y3Y is heteroaryl) or xe2x80x94CH2xe2x80x94Y3Y wherein Y3Y is as previously defined)
(with the proviso that, definitions not related are omitted) have an inhibitory activity on IL-1xcex2 release (see WO 93/09135).
Further, it is disclosed that compounds of formula (Z):
RZxe2x80x94A1Zxe2x80x94A2Zxe2x80x94XZxe2x80x94A3Zxe2x80x83xe2x80x83(Z)
wherein
RZ is hydrogen, an amino or hydroxy protecting group or benzyloxy which may be optionally substituted by a ring;
A1Z is an xcex1-hydroxy acid, amino acid residue or thiocarbonyl analogue, each with an optionally protected side chain, or 
(in which ring AZ may be optionally substituted by hydroxy or C1-4 alkoxy and RaZ is CO or CS);
A2Z is an xcex1-hydroxy acid, xe2x80x94NHxe2x80x94CHR3Zxe2x80x94COxe2x80x94 (in which R3Z is an optionally protected side chain of an xcex1-amino acid);
XZ is 
xe2x80x83,or 
(in which R7Z is xe2x80x94CO2H, xe2x80x94CONHOH or a bioisosteric group); and
A3Z is xe2x80x94CH2xe2x80x94X1Zxe2x80x94COxe2x80x94Y1Z, xe2x80x94CH2xe2x80x94Oxe2x80x94Y2Z or xe2x80x94CH2xe2x80x94Sxe2x80x94Y3Z (in which X1Z is O or S, Y1Z is an aliphatic ring, optionally substituted with aryl, diphenylmethyl, optionally substituted by a ring, piperidino or optionally substituted mono, di or tricyclic heteroaryl, Y2Z is an aliphatic ring, diphenylmethyl, optionally substituted by a ring, or optionally substituted di or tricyclic heteroaryl etc. and Y3Z is an aliphatic ring, tri-(C1-4 alkyl)methylcarbonyl, di-(C1-4 alkyl) aminothiocarbonyl, 4-nitrophenyl, 2,6-dichloro-benzoyl, 2,3,6-trichloro-4-pyridyl, 5-membered heterocyclic ring containing a nitrogen atom or optionally substituted di or tricyclic heteroaryl, etc.) etc.; and
A1Z and A2Z may form 
(in which R1aZ and R5Z together make form C2-5 alkylene or C2-5 alkenylene and Y5Z is an optionally protected side chain of an xcex1-amino acid, etc.)
(with the proviso that, definitions not related are omitted) have an inhibitory activity on IL-1xcex2 release (see EP 618223).
Furthermore, it is disclosed that compounds of formula (W): 
wherein
nW is 0-4;
YW is 
xe2x80x83wherein when R3W is O, YW is 
(in which R2W is hydrogen or deuterium;
R3W is O, OH, OR6W, NR6W OR7W or NR6WR7W;
R6W and R7W each, independently, is hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
R4W is hydrogen or alkyl;
R5W is hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, haloalkyl, nitro or cyano, HETW is heteroaryl);
AAW is 
(in which R6W and R7W have the same meaning as hereinbefore defined and
R11W is (CR6WR7W)0-6xe2x80x94R12W (wherein R12W is aryl, heteroaryl or optionally selected from hereinbefore described R5W)) or an amino acid; and
R1W is R12Wxe2x80x94COxe2x80x94 or R12WSO2xe2x80x94 (wherein R12W has the same meaning as hereinbefore defined)
(with the proviso that, definitions not related are omitted) have an inhibitory activity on IL-1xcex2 converting enzyme (see CA 2125021)
Energetic investigations have been carried out to discover new compounds having inhibitory activity on IL-1xcex2 converting enzyme. As a result, the present inventors have achieved that goal by a tetrazole compound of formula (I).
The tetrazole compounds of the present invention are newly synthesized and therefore, are quite novel.
To summarize, in the compound of formula (X) known in the art (EP 519748), R6X of YX can represent aryl C1-6 alkyl. But, the aryl group does not include a tetrazole. On the other hand, in the compound of the present invention, Y essentially is the tetrazole group. Therefore, it can be said that the compounds of the present invention have a chemical structure quite different from the compounds of formula (X). A representative example of formula (X) is compound (X-1). 
In the compound of formula (Y) of WO93/09135, Y3Y of A5Y can be a heteroaryl group. Further, exemplification of the heteroaryl group includes a tetrazole group. But, no substituents of the heteroaryl group are disclosed in detail in WO93/09135. On the other hand, a compound of the present invention has a ring essentially as substituents of the tetrazole of Y. It can be said that the compounds of the present invention have a chemical structure quite different from the compounds of formula (Y). Representative examples of formula (Y) are compounds (Y-1) and (Y-2). 
Further, in a compound of formula (Z), EP 618223, Y3Z of A3Z can represent a heteroaryl group. Further, exemplification of the heteroaryl group includes a tetrazole. But, only C1-4 alkyl is disclosed as substituents of the heteroaryl group. On the other hand, a compound of the present invention has a ring as a substituent of the tetrazole of Y. Therefore, it can be said that the compounds of the present invention have a chemical structure quite different from the compounds of formula (Z). Furthermore, in the compounds of formula (Z), Y3Z as a heteroaryl group is essentially bonded to a hetero atom (oxygen or sulfur atom). On the other hand, in the present invention, the tetrazole group of Y is bonded to a carbon atom. Thus, for another reason, compounds of formula (I) of the present invention have a chemical structure quite different from a compound of formula (Z). A representative example of a compound of formula (Z) is compound (Z-1). 
Furthermore, in the compounds of formula (W) of CA 21 25021, HETW of YW can be a heteroaryl group. Further, exemplification of the heteroaryl group includes a tetrazole group. But, there are no preparative examples of compounds in which a heteroaryl group is a tetrazole. Additionally, in the compound of formula (W), HETW as a heteroaryl is bonded to a hetero atom (oxygen atom). On the other hand, in the present invention, the tetrazole group Y is bonded to a carbon atom. Thus, compounds of formula (I) of the present invention have a chemical structure quite different from compound of formula (W). A representative compound of formula (W) is compound (W-1). 
Therefore, the compounds of the present invention have a chemical structure quite different from the compounds of formulae (X), (Y), (Z) and (W) known in the art. The instant compounds are novel and not previously described.
Therefore, the present inventors-have found that tetrazole compounds of formula (I) have an inhibitory activity on IL-1xcex2 converting enzyme even if a hetero atom dose not exist between a ketone group and a ring. That observation is quite unexpected from what is known in the art, and has been confirmed from experiments by the present inventors for the first time.
The present invention is related to:
1) A tetrazole derivatives of the formula (I) 
xe2x80x83wherein R is a hydrogen atom, 
(in which J is bond, C1-6 alkylene, C1-6 oxyalkylene, C1-6 aminoalkylene, C1-6 thioalkylene, C2-6 alkenylene, carbocyclic ring or hetero ring, carbocyclic ring and hetero ring may be substituted by C1-4 alkyl, with the proviso that, when J contains oxygen, nitrogen or sulfur atom, it is bond to Cxe2x95x90O or S(O)m group in R),
R1 is
1) C1-8 alkyl,
2) C1-8 alkoxy,
3) C2-8 alkenyl,
4) C2-8 alkenyloxy,
5) C1-8 alkylamino,
6) di(C1-8 alkyl)amino,
7) C1-8 alkylthio,
8) Cyc1 (in which Cyc1 is a carbocyclic ring or hetero ring, and Cyc1 may be substituted by 1 to 5 substituents selected from a hydrogen atom, C1-8 alkyl, phenyl, phenyloxy, C1-8 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, keto, xe2x80x94OR2, xe2x80x94NR2R3, xe2x80x94S(O)R2, xe2x80x94SO2R2, xe2x80x94COOR or xe2x80x94COR2, wherein R2 is a hydrogen atom, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl, R3 is a hydrogen atom, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl, C2-5 acyl, or R2 and R3, taken together bonded to nitrogen atom, represent hetero ring),
9) Cyc1xe2x80x94Oxe2x80x94,
10) Cyc1xe2x80x94Sxe2x80x94,
11) Cyc1xe2x80x94COxe2x80x94,
12) C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino, di(C1-8 alkyl)amino or C1-8 alkylthio mono or di-substituted by Cyc1, Cyc1xe2x80x94Oxe2x80x94, Cyc1xe2x80x94Sxe2x80x94, or Cyc1xe2x80x94COxe2x80x94,
13) trifluoromethyl,
14) Cyc1xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94,
15) amino,
16) benzyloxycarbonyl,
17) C2-5 acylamino, or
18) C1-8 alkoxy substituted by C1-8 alkoxy,
m is 0 or 1-2,
with the proviso that,
(1) when m is 0, then xe2x80x94S(O)mxe2x80x94 is not directly bonded to nitrogen or sulfur atom, and
(2) when m is 1, then xe2x80x94S(O)mxe2x80x94 is not directly bonded to sulfur atom,
AA1 is
1) a bond or
2) 
(in which R4 is
(1) a hydrogen atom,
(2) C1-8 alkyl,
(3) Cyc2 (in which Cyc2 is a carbocyclic ring or hetero ring, and Cyc2 may be substituted by 1 to 5 substituents selected from a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, tetrazole, xe2x80x94OR5, xe2x80x94NR5R6, xe2x80x94SR5, xe2x80x94COOR5 or xe2x80x94COR5 wherein R5 and R6 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl) or
(4) C1-8 alkyl substituted by a substituent selected from xe2x80x94OR7, xe2x80x94NR7R8, xe2x80x94SR7, COOR7, xe2x80x94COR7, xe2x80x94CONH2, xe2x80x94NR7xe2x80x94COxe2x80x94NR7R8, guanidino or Cyc2 (in which R7 and R8 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl),
AA2 is
1) a bond or
2) 
(in which R9 and R10 each, independently, is
(1) a hydrogen atom,
(2) C1-8 alkyl,
(3) Cyc3 (in which Cyc3 is a carbocyclic ring or hetero ring, and Cyc3 may be substituted by 1 to 5 substituents selected from a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, tetrazole, xe2x80x94OR11, xe2x80x94NR11R12, xe2x80x94SR11, xe2x80x94COOR11 or xe2x80x94COR11, wherein R11 and R12 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl),
(4) C1-8 alkyl substituted by a substituent selected from xe2x80x94OR13, xe2x80x94NR13R14, xe2x80x94SR13, xe2x80x94COOR13, xe2x80x94COR13, xe2x80x94CONH2, xe2x80x94NR13xe2x80x94COxe2x80x94NR13R14, guanidino or Cyc3 (in which R13 is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl, R14 is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 alkyl substituted by phenyl, t-butyloxycarbonyl or benzyloxycarbonyl) or
(5) R9 and R10, together, is a C1-6 alkylene or C2-6 alkenylene),
AA1 and AA2, together, may have the formula 
in which R15 and R16 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl (with the proviso that, C1-4 alkyl or phenyl may be substituted by C1-4 alkyl, C1-4 alkoxy, a halogen atom, trifluoromethyl or phenyl),
R17 is
(1) a hydrogen atom,
(2) C1-8 alkyl,
(3) Cyc3 (in which Cyc3 has the same meaning as hereinbefore defined) or
(4) C1-8 alkyl substituted by a substituent selected from xe2x80x94OR13, xe2x80x94NR13R14, xe2x80x94SR13, xe2x80x94COOR13, xe2x80x94COR13, xe2x80x94CONH2, xe2x80x94NR13xe2x80x94COxe2x80x94NR13R14, guanidino or Cyc3 (in which R13 and R14 have the same meaning as hereinbefore defined),
q is 2-12,
with the proviso that, a carbon atom in xe2x80x94(CH2)qxe2x80x94 may be replaced by an oxygen atom, sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR18xe2x80x94 (in which R18 is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl), or
two hydrogen atom at ortho positions are replaced by a double bond and
Y is 
in which R19 is a hydrogen atom, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl,
n is 1-4, 
xe2x80x83is 
xe2x80x83or 
Z is
1) C1-6 alkylene,
2) C2-6 alkenylene,
3) oxygen atom,
4) sulfur atom,
5) xe2x80x94COxe2x80x94,
6) xe2x80x94SOxe2x80x94,
7) xe2x80x94SO2xe2x80x94,
8) xe2x80x94NR26xe2x80x94 (in which R26 is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 alkyl substituted by phenyl), or
9) a carbon atom in C1-6 alkylene replaced by an oxygen atom, sulfur atom, xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR26xe2x80x94 (in which R26 is the same meaning as hereinbefore defined),
with the proviso that, Z is bonded directly to the carbon atom on a tetrazole ring,
E is a hydrogen atom, a halogen atom, C1-4 alkyl, xe2x80x94COOR27 (in which R27 is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 substituted by phenyl), xe2x80x94CONR28R29 (in which R28H and R29 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 substituted by phenyl or R28 and R29, taken together, boned to nitrogen atom represent hetero ring), xe2x80x94NR28R29 (in which R28 and R29 are the same meaning as hereinbefore defined), or 
xe2x80x83(in which 
xe2x80x83is carbocyclic ring or hetero ring,
R20 is
1) a hydrogen atom,
2) C1-8 alkyl,
3) a halogen atom,
4) nitro,
5) trifluoromethyl,
6) nitrile,
7) xe2x80x94OR22,
8) xe2x80x94NR22R23,
9) xe2x80x94SR22,
10) xe2x80x94COOR22,
11) xe2x80x94COR22,
12) xe2x80x94CONR28R29 (in which R28 and R29 are the same meaning as hereinbefore defined),
13) Cyc4 (in which Cyc4 is a carbocyclic ring or hetero ring, and Cyc4 may be substituted by 1 to 5 substituents selected from a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, a halogen atom, nitro, trifluoromethyl, nitrile, tetrazole, xe2x80x94OR24, xe2x80x94NR24R25, xe2x80x94SR24, xe2x80x94COOR24 or xe2x80x94COR24 (in which R24 and R25 each, independently, is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl)), or
14) C1-8 alkyl substituted by Cyc4 (in which Cyc4 is the same meaning as hereinbefore defined),
R22 is a hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted by phenyl,
R23 is a hydrogen atom, C1-4 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C2-5 acyl or trifluoromethylcarbonyl,
p is 1-5), or
xe2x80x94Zxe2x80x94E is a halogen atom, trifluoromethyl, C1-4 alkyl di-substituted by phenyl or tri(C1-4 alkyl)silyl,
with the proviso that,
(1) when Z is C1-6 alkylene or C2-6 alkenylene, then E is not a hydrogen atom or C1-4 alkyl, or
(2) when Z is xe2x80x94SOxe2x80x94, then E is not a hydrogen atom, or a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof,
2) processes for the preparation thereof and
3) pharmaceutical agents containing such a derivative as an active ingredient.
Throughout the specification, including claims, it may be easily understood by those skilled in the art, that all isomers are included in the present invention. For example, the alkyl, alkoxy and alkylene groups include straight-chain and also branched-chain ones. Accordingly, all isomers produced by the existence of asymmetric carbon atoms are included in the present invention when branched-chain alkyl, alkoxy, alkylene, etc. exist.
In formula (I), C1-8 alkyl represented by substituent of Cyc1, substituent of Cyc2, substituent of Cyc3, R1, R2, R3, R4, R9, R10, R17, R19 and R20, C1-8 alkyl mono or di-substituted by Cyc1, Cyc1xe2x80x94Oxe2x80x94, Cyc1xe2x80x94Sxe2x80x94 or Cyc1xe2x80x94COxe2x80x94, C1-8 alkyl substituted by Cyc4, C1-8 alkyl substituted by a group selected from xe2x80x94OR7, xe2x80x94NR7R8, xe2x80x94SR7, xe2x80x94COOR7, xe2x80x94COR7, xe2x80x94CONH2, xe2x80x94NR7xe2x80x94COxe2x80x94NR8, guanidino and Cyc2 and C1-8 alkyl substituted by a group selected from xe2x80x94OR13, xe2x80x94NR13R14, xe2x80x94SR13, xe2x80x94COOR13, xe2x80x94COR13, xe2x80x94CONH2, xe2x80x94NR13xe2x80x94COxe2x80x94NR14, guanidino and Cyc3 each means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and an isomer thereof.
In formula (I), C1-8 alkylamino represented by R1 and C1-8 alkylamino mono or di-substituted by Cyc1, Cyc1xe2x80x94Oxe2x80x94, Cyc1xe2x80x94Sxe2x80x94 or Cyc1xe2x80x94COxe2x80x94 each means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and an isomer thereof, which are substituted by an amino group.
In formula (I), di(C1-8 alkyl)amino represented by R1 and di(C1-8 alkyl)amino mono or di-substituted by Cyc1, Cyc1xe2x80x94Oxe2x80x94, Cyc1xe2x80x94Sxe2x80x94 or Cyc1xe2x80x94COxe2x80x94 each means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and an isomer thereof, which are each independently di-substituted by an amino group on nitrogen atom.
In formula (I), C1-8 alkylthio represented by R1 and C1-8 alkylthio mono or di-substituted by Cyc1, Cyc1xe2x80x94Oxe2x80x94, Cyc1xe2x80x94Sxe2x80x94 or Cyc1xe2x80x94COxe2x80x94 each means thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, thioheptyl, thiooctyl and an isomer thereof.
In formula (I), C1-8 alkoxy represented by R1 and C1-8 alkoxy mono or di-substituted by Cyc1, Cyc1xe2x80x94Oxe2x80x94, Cyc1xe2x80x94Sxe2x80x94 or Cyc1xe2x80x94COxe2x80x94 each means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and an isomer thereof.
In formula (I), C1-8 alkoxy substituted by C1-8 alkoxy represented by R1 means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomer thereof, which are substituted by a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomer thereof.
In formula (I), C1-4 alkyl represented by a substituent of carbocyclic ring , substituent of hetero ring, substituent of R15, substituent of R16, R5, R6, R7, R8, R11, R12, R13, R14, R15, R16, R18, R22, R23, R24, R25, R26, R27, R28, R29 and E means methyl, ethyl, propyl, butyl and an isomer thereof.
In formula (I), C1-4 alkoxy represented by R15 and R16 mean methoxy, ethoxy, propoxy, butoxy and an isomer thereof.
In formula (I), C1-4 alkyl substituted by phenyl represented by substituent of Cyc2, substituent of Cyc3, substituent of Cyc4, R2, R3, R5, R6, R7, R8, R11, R12, R13, R14, R15, R16, R18, R19, R22, R23, R24, R25, R26, R27, R28 and R29 means methyl, ethyl, propyl, butyl and the isomer thereof, which are substituted by a phenyl group.
In formula (I), C1-8 alkyl substituted by phenyl represented by substituent of Cyc1 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomer thereof, which are substituted by a phenyl group.
In formula (I), a halogen atom represented by a substituent of R15 and R16, substituent of Cyc1, substituent of Cyc2, substituent of Cyc3, substituent of Cyc4, R20, E and xe2x80x94Zxe2x80x94E means fluorine, chlorine, bromine and iodine.
In formula (I), C1-6 alkylene represented by J, Z, and R9 and R10, taken together, means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and an isomer thereof.
In formula (I), C1-6 oxyalkylene represented by J means oxymethylene, oxyethylene, oxytrimethylene, oxytetramethylene, oxypentamethylene, oxyhexamethylene and an isomer thereof.
In formula (I), C1-6 aminoalkylene represented by J means aminomethylene, aminoethylene, aminotrimethylene, aminotetramethylene, aminopentamethylene, aminohexamethylene and an isomer thereof.
In formula (I), C1-6 thioalkylene represented by J means thiomethylene, thioethylene, thiotrimethylene, thiotetramethylene, thiopentamethylene, thiohexamethylene and an isomer thereof.
In formula (I), C2-6 alkenylene represented by J, Z, and R9 and R10, taken together, means vinylene, propenylene, butenylene, pentenylene, hexenylene, butadienylene, pentadienylene, hexadienylene, hexatrienylene and an isomer thereof.
In formula (I), C2-8 alkenyl represented by R1 means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and an isomer thereof.
In formula (I), C2-8 alkenyloxy represented by R1 means vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, butadienyloxy, pentadienyloxy, hexadienyloxy, heptadienyloxy, octadienyloxy, hexatrienyloxy, heptatrienyloxy, octatrienyloxy and an isomer thereof.
In formula (I), C2-5 acyl represented by R3 and R23 means acetyl, propionyl, butyryl, valeryl and an isomer thereof.
In formula (I), C2-5 acylamino represented by R1 means acetylamino, propionylamino, butyrylamino, valerylamino and an isomer thereof.
In formula (I), tri(C1-4 alkyl)silyl represented by xe2x80x94Zxe2x80x94E means each independent tri-substituted by methyl, ethyl, propyl, butyl and the isomer thereof, on silicon atom.
In formula (I), a carbocyclic ring represented by J Cyc1, Cyc2, Cyc3, Cyc4 and 
means a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring. For example, a 3-10 membered mono-cyclic or bi-cyclic carbocyclic ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentadiene, benzene, pentalene, indene, naphthalene, azulene ring etc.
In formula (I), a hetero ring represented by J, Cyc1, Cyc2, Cyc3, Cyc4 and 
means a 5-18 membered mono-cyclic, bi-cyclic or tri-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom or one sulfur atom. For example, a 5-18 membered mono-cyclic, bi-cyclic or tri-cyclic hetero ring containing 1-3 nitrogen atoms, one oxygen atom or one sulfur atom includes pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiazoe, thiaine (thiopyran), thiepine, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiazoe, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisooxazole, tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthatazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, benzooxazepine, benzooxadiazepine, benzothiazepine, benzodithiazepine, benzoazepine, benzodiazepine, indolooxoazepine, indolotetrahydrooxazepine, indolooxadiazepine, indolotetrahydrooxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, camphere, imidazothiazole ring etc.
In formula (I), hetero ring represented by R2 and R3, taken together bonded to nitrogen atom, and R28 and R29, taken together bonded to nitrogen atom, means a 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom or one sulfur atom. For example, a 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom or one sulfur atom includes pyrroline pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyrimidine, tetrahydropyridazine ring etc.
In formula (I), 
represented by AA1 may be an xcex1-amino acid residue. For example, glycine, alanine, serine, threonine, cystine, valine, methionine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, arginine, glutamine, lysine, histidine etc.
In formula (I), 
represented by AA2 may be an xcex1-amino acid residue. For example, glycine, alanine, serine, threonine, cystine, valine, methionine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, arginine, glutamine, lysine, histidine, proline etc.
In formula (I), C1-4 alkyl di-substituted by phenyl represented by xe2x80x94Zxe2x80x94E means methyl, ethyl, propyl, butyl and the isomer thereof, which are disubstituted by phenyl group.
In formula (I), keto group represented by substituent of Cyc1 may be substituted at one carbon atom, one nitrogen atom, or one or two sulfar atom.
In the present invention, non-toxic salts includes all such salts. For example, the following salt, acid addition salt or hydrate, etc.
Salt
The compounds of formula (I) of the present invention in the case of free carboxylic acid or tetrazole may be converted into a corresponding non-toxic salt by methods known per se. Non toxic and water-soluble salts are preferable. Suitable salts, for example, are salts of an alkaline metal (potassium, sodium etc.), salts of an alkaline earth metal (calcium, magnesium etc.), ammonium salts and salts of pharmaceutically-acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine etc.).
Acid Additional Salt
The compounds of formula (I) of the present invention may be converted into a corresponding acid addition salt by methods known per se. Non toxic and water-soluble salts are preferable. Suitable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
Hydrate
The compounds of formula (I) or salts thereof of the present invention may be converted into a corresponding hydrate by methods known per se.
Preferred compounds of the present invention are as follows: tetrazole derivative of formula I (1) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (2) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (3) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (4) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (5) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (6) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (7) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (8) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (9) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (10) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (11) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (12) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (13) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (14) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (15) 
(wherein R4 R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (16) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula i (17) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (18) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (19) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (20) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (21) 
(wherein R15, R16, R17 and (CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (22) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (23) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (24) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (25) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (26) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (27) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (28) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (29) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (30) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (31) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (32) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (33) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (34) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (35) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (36) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (37) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (38) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (39) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (40) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (41) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (42) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (43) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (44) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (45) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (46) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound of formula I (47) 
(wherein R4, R9 and R10 have the same meaning as hereinbefore defined), the compound formula I (48) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (49) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (50) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (51) 
(wherein R15, R16, R17 and xe2x80x94(CH2)qxe2x80x94 have the same meaning as hereinbefore defined), the compound of formula I (52) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (53) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (54) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (55) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (56) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (57) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (58) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (59) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (60) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (61) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (62) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (63) 
(wherein Y has the same meaning as hereinbefore defined), the compound of formula I (64) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (65) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (66) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (67) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (68) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (69) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (70) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (71) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (72) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (73) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (74) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (75) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (76) 
(wherein R1 has the same meaning as hereinbefore defined), the compound of formula I (77) 
(wherein R1 has the same meaning as hereinbefore defined) or a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof.
Examples of representative compounds of formula (I) of the present invention are listed in Table 1-77 or a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof and described in example.
Processes for the Preparation
For compounds of formula (I) of the present invention, those in which R does not contain a COOH group, AA1 does not contain a COOH group, AA2 does not contain a COOH group and Y does not contain a COOH group, i.e., the compounds of formula (I-A) 
wherein RA, AA1A, AA2A and YA have the same meaning as hereinbefore defined for R, AA1, AA2 and Y, respectively, provided that all of RA, AA1A, AA2A and YA do not contain a COOH group may be prepared by methods (a) to (b) as follows.
(a) For compounds of formula (I-A) of the present invention, those in which RA does not contain an amino group, AA1A does not contain an amino group, AA2A does not contain an amino group, YA does not contain an amino group and xe2x80x94Zxe2x80x94E group is bonded directly to a carbon atom of tetrazole of YA,i.e., the compounds of formula (I-A-a) 
wherein RA-a, AA1A-a, AA2A-a and YA-a have the same meaning as hereinbefore defined for RA, AA1A, AA2A and YA respectively, provided that all of RA-a, AA1A-a, AA2A-a and YA-a do not contain an amino group and xe2x80x94Zxe2x80x94E group is bonded directly to a carbon atom of tetrazole of YA-a may be prepared by methods (a-1), (a-2), (a-3) or (a-4) as follows.
(a-1) For compounds of formula (I-A-a) of the present invention, those in which xe2x80x94Zxe2x80x94E do not tri(C1-4 alkyl)silyl, i.e., the compounds of formula (I-A-a-1) 
wherein YA-a-1 have the same meaning as hereinbefore defined for YA-a, provided that of YA-a-1 do not tri(C1-4 alkyl)silyl, the other symbols are the same meaning as hereinbefore defined may be prepared by reacting a compound of formula (II-a-1) 
wherein R19A is C1-8 alkyl, phenyl or C1-4 alkyl substituted with phenyl, XA-a-1 is a leaving group known per se (e.g., chlorine, bromine or iodine atom, mesyl, tosyl group etc.) and the other symbols have the same meaning as hereinbefore defined with a compound of formula (III-a-1) 
wherein ZA-a-1 and EA-a-1 has the same meaning as hereinbefore defined for Z and E, provided that xe2x80x94ZA-a-1xe2x80x94EA-a-1 do not contain COOH, amino groups and tri(C1-4 alkyl)silyl group.
This reaction is known per se, and may be carried out, for example, in an organic solvent (e.g., N,N-dimethylformamide etc.), in the presence of potassium fluoride etc., at a temperature of from 20xc2x0 C. to 40xc2x0 C.
(a-2) For compounds of formula (I-A-a) of the present invention, those in which xe2x80x94Zxe2x80x94E represent tri(C1-4 alkyl)silyl, i.e., the compounds of formula (I-A-a-2) 
wherein YA-a-2 have the same meaning as hereinbefore defined for YA-a, provided that of xe2x80x94Zxe2x80x94E group in YA-a-2 represent tri(C1-4 alkyl)silyl, the other symbols are the same meaning as hereinbefore defined may be prepared by reacting a compound of formula (II-a-2) 
wherein G is C1-4 alkyl and the other symbols have the same meaning as hereinbefore defined with a compound of formula (III-a-2) 
wherein RIII-a-2-1, RIII-a-2-2 and RIII-a-2-3 is each independently C1-4 alkyl.
This reaction is known per se, and may be carried out, for example, the same method described in Chem. Pharm. Bull., 30, 3450-3452 (1982). For example, this reaction carried out by reacting the compound of the formula (III-a-2) with alkylaminolithium (e.g., lithium diisobutylamide [LDA], etc.) in an inert organic solvent (e.g., diethyl ether, tetrahydrofuran etc.) under an atomoshere inert gas (e.g., argon, nitrogen, etc.) at a temperature of from xe2x88x9220xc2x0 C. to 0xc2x0 C., and then by reacting the obtained lithium compound with the compound of the formula (II-a-2) at a temperature of from xe2x88x9220xc2x0 C. to 0xc2x0 C.
(a-3) For compounds of formula (I-A-a) of the present invention, those in which RA-a and NH group in AA1A-a or AA2A-a bonded to form amide bond, sulfonamide bond or sulfonylurea bond, i.e., the compounds of formula (I-A-a-3) 
wherein RA-a-3, AA1A-a-3 and AA2A-a-3 have the same meaning as hereinbefore defined for RA-a, AA1A-a and AA2A-a, provided that of RA-a-3 and NH group in AA1A-a-3, AA2A-a-3 and YA-a bonded to form amide bond, sulfonamide bond or sulfonylurea bond, the other symbols are the same meaning as hereinbefore defined may be prepared by reacting a compound of formula (II-a-3) 
wherein XA-a-3 is a leaving group (e.g., chlorine, bromine or iodine atom etc.) or a hydroxy group and the other symbols have the same meaning as hereinbefore defined with a compound of formula (III-a-3)
H2Nxe2x80x94YA-axe2x80x83xe2x80x83(III-a-3)
wherein all the symbols have the same meaning as hereinbefore defined.
The reaction can be carried out as an amidation reaction, sulfonamidation reaction, sulfonylurea reaction and the like.
Amidation reactions are known per se and can be carried out by, for example:
(1) using an acid halide,
(2) using a mixed acid anhydride,
(3) using a condensing agent etc.
Each of those methods can be carried out, for example, as follows:
(1) the method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (e.g., oxalyl chloride, thionyl chloride etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the acid halide obtained with an amine in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.,
(2) the method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (e.g., pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (e.g., ethyl chloroformate, isobutyl chloroformate etc.) in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at a temperature of from 0xc2x0 C. to 40xc2x0 C., and then by reacting the mixture of acid anhydride obtained with an amine in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C., or
(3) the method using a condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 2-chloro-1-methylpyridinium iodide etc.) may be carried out, for example, by reacting a carboxylic acid with an amine using a condensing agent in the presence or absence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, dimethyl formamide, diethyl ether etc.) or without a solvent at a temperature of from 0xc2x0 C. to 40xc2x0 C.
The reactions (1), (2) and (3) hereinbefore described preferably may be carried out in an atmosphere of inert gas (e.g., argon, nitrogen etc.) under anhydrous conditions.
Sulfonamidation reactions are known pre se, and can be carried out, for example, by reacting a sulfonic acid derivatives with an acid halide (e.g., oxalyl chloride, thionyl chloride, phosphous trichloride, phosphous pentachloride etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the sulfonyl halide obtained with an amine in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Formation of sulfonylurea reactions are known pre se, and can be carried out, for example, by reacting a aminosulfonic acid derivatives with an acid halide (e.g., oxalyl chloride, thionyl chloride, phosphous trichloride, phosphous pentachloride etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the aminosulfonyl halide obtained with an amine in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(a-3) For compounds-of formula (I-A-a) of the present invention, those in which RA-a and NH group in AA1A-a or AA2A-a bonded to form urea bond, i.e., the compounds of formula (I-A-a-4) 
wherein R1A-a-3, JA-a-4, AA1A-a-4 and AA2A-a-4 have the same meaning as hereinbefore defined for R1, J, AA1A-a and AA2A-a, provided that of R1A-a-4xe2x80x94JA-a-4 group do not contain an COOH, amino group, and carbonyl bonded to NH group in R1A-a-4xe2x80x94JA-a-4, the other symbols are the same meaning as hereinbefore defined may be prepared by reacting a compound of formula (II-a-4) 
wherein all the symbols have the same meaning as hereinbefore defined with a compound of formula (III-a-4)
R1A-a-4xe2x80x94JA-a-4xe2x80x94Hxe2x80x83xe2x80x83(III-a-4)
wherein all the symbols have the same meaning as hereinbefore defined.
Formation of urea reactions are known pre se, and can be carried out, for example, in an inert organic solvent (e.g., dimethylformamide, dichloromethane, tetrahydrofuran etc.), using N,Nxe2x80x2-carbodiimidazole, an amine in the presence or absence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.), at a temperature of from 0xc2x0 C. to 80xc2x0 C.
(b) For compounds of formula (I-A) of the present invention, those in which at least one of RA, AA1A, AA2A and YA represent contains an amino group i.e., the compounds of formula (I-A-b) 
wherein RA-b, AA1A-b, AA2A-b and YA-b have the same meaning as hereinbefore defined for RA, AA1A, AA2A and YA, respectively, provided that at least one of RA-b, AA1A-b, AA2A-b and YA-b represent contains an amino group may be prepared by methods (b-1) or (b-2) as follows.
(b-1) For compounds of formula (I-A-b) of the present invention may be prepared by subjecting the amino protecting group to elimination, the compound prepared by the same methods (a-1), (a-2), (a-3) or (a-4) above and protecting an amino group as known per se (e.g., t-butyloxycarbonyl, benzyloxycarbonyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl or trifluoroacetyl etc.), i.e., the compound of formula (II-b-1) 
wherein RA-IIb-1, AA1A-IIb-1, AA2A-IIb-1 and YA-IIb-1 have the same meaning as hereinbefore defined for RA-b, AA1A-b, AA2A-b and YA-b respectively, provided that at least one of RA-IIb-1, AA1A-IIb-1, AA2A-IIb-1 and YA-IIb-1 represent contains a protected amino group with a known protecting group (e.g., t-butyloxycarbonyl, benzyloxycarbonyl, triphenylmethyl, 2-(trimethylsilyl) ethoxymethyl or trifluoroacetyl etc.).
The elimination of an amino protecting group May be carried out by methods known per se, and depends on the protecting group. For example, when the protecting group is t-butoxycarbonyl, triphenylmethyl or 2-(trimethylsilyl)ethoxymethyl, the reaction may be carried out in a water-miscible organic solvent (e.g., methanol, tetrahydrofuran, dioxane, acetone etc.) in the presence of aqueous solution of organic acid (e.g., acetic acid, trifluoroacetic acid etc.) or inorganic acid (hydrochloric acid, sulfuric acid etc.) or a mixture of them, at a temperature of from 0xc2x0 C. to 100xc2x0 C.
When the protecting group is a benzyloxycarbonyl group, the elimination of the protecting group can be carried out by hydrogenation. The hydrogenation reaction is known per se, and may be carried out, for example, in an inert solvent [ether (e.g., tetrahydrofuran, dioxane, diethoxyethane, diethyl ether etc.), alcohol (e.g., methanol, ethanol etc.), benzene analogues (e.g., benzene, toluene etc.), ketone (e.g., acetone, methyl ethyl ketone etc.), nitrile (e.g., acetonitrile etc.), amide (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid, mixture of two or more of them etc.], in the presence of a catalyst of hydrogenation (e.g., palladium on activated carbon, palladium black, palladium, palladium hydroxide on carbon, platinum oxide, nickel, Raney nickel (registered trade mark) etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid etc.), at ordinary or additional pressure under an atmosphere of hydrogen, at a temperature of from 0xc2x0 C. to 200xc2x0 C. When using an acid, its salt may be used at the same time.
Furthermore, when the protecting group is a trifluoroacetyl group, may be carried out, for example, in a water-miscible organic solvent (e.g., methanol, tetrahydrofuran, dioxan, acetone etc.), using a hydroxide of an alkali metal (e.g., sodium hydroxide, potassium hydroxide, etc.), hydroxide of an alkaline earth metal (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate of an alkali metal (e.g., sodium carbonate, potassium carbonate, etc.), or aqueous solution thereof, at a temperature of from 0xc2x0 C. to 40xc2x0 C.
It should be easily understood by those skilled in the art, that other amino protecting groups that can be used in the present invention are available and the choices are not limited only to t-butyloxycarbonyl, benzyloxycarbonyl, triphenylmethyl, 2-(trimethylsilyl) ethoxymethyl or trifluoroacetyl groups. Any group which can be easily and selectively eliminated essentially can be used. For example, a protecting group may be one described in Protective Groups in Organic Synthesis (T. W. Greene, Wiley, New York (1991)). The proposed compounds of the present invention may be easily prepared with those protecting group practicing known methods.
(b-2) For compounds of formula (I-A-b) of the present invention may be prepared by subjecting reduction, the compound prepared by the same methods (a-1), (a-2), (a-3) or (a-4) above and having nitro group, i.e., the compound of formula (II-b-2) 
wherein RA-IIb-2, AA1A-IIb-2, AA2A-IIb-2 and YA-IIb-2 have the same meaning as hereinbefore defined for RA-b, AA1A-b, AA2A-b and Ya-b, respectively, provided that at least one of RA-IIb-2, AA1A-IIb-2, AA2A-IIb-2 and YA-IIb-2 contains a nitro group.
Reduction of nitro group is known per se, and may be carried out, hydrogenation or reduction by using organic metal.
Hydrogenation may be carried out by the same method as hereinbefore described.
Reduction by using organic metal is known per se, and may be carried out, for example, in a water-miscible organic solvent (e.g., ethanol, methanol etc.), in the presence or absence of an aqueous solution of hydrochloric acid, by using organic metal (e.g., zinc, iron, tin, tin chloride, iron chloride, etc.), at a temperature of from 50xc2x0 C. to 150xc2x0 C.
For compounds of formula (I) of the present invention, those in which at least one of R, AA1, AA2 and Y represent contain a COOH group, i.e., the compounds of formula (I-B) 
wherein RB, AA1B, AA2B and YB have the same meaning as hereinbefore defined for R, AA1, AA2 and Y, respectively, provided that at least one of RB, AA1B, AA2B and YB represent contains a COOH group may be prepared by, for example, hydrolysis of a t-butylester, hydrogenation, hydrolysis of an ester or a cleavage reaction of a 2,2,2-trichloroethylester group of a compound having at least one COOH group derivatized to contain a t-butylester, benzylester, alkylester or 2,2,2-trichloroethylester i.e., the compound of formula (I-A-1) 
wherein RA-1, AA1A-1, AA2A-1 and YA-1 have the same meaning as hereinbefore defined for RA, AA1A, AA2A and YA, respectively, provided that at least one of RA-1, AA1A-1, AA2A-1 and YA-1 represent contains a t-butylester, benzylester, alkylester or 2,2,2-trichloroethylester group.
Hydrolysis of t-butylester is known per se, and may be carried out, for example, in an inert organic solvent (e.g., dichloromethane, chloroform, methanol, dioxane, ethyl acetate, anisole etc.) in the presence of an organic acid (e.g., trifluoroacetic acid etc.), or inorganic acid (e.g., hydrochloric acid etc.) or a mixture of them, at a temperature of from 0xc2x0 C. to 90xc2x0 C.
Hydrogenation may be carried out by the same method as hereinbefore described.
Hydrolysis of an ester is known per se, and may be carried out, for example, by hydrolysis in acid or under alkaline conditions. Hydrolysis under alkaline conditions may be carried out, for example, in an appropriate organic solvent (e.g., methanol, dimethoxyethane etc.), using a hydroxide or a carbonate of an alkali metal or alkaline earth metal, at a temperature of from 0xc2x0 C. to 40xc2x0 C. Hydrolysis under acidic conditions may be carried out by the same method as for hydrolysis of a t-butylester.
Cleavage of 2,2,2-trichloroethylester is known per se, and may be carried out, for example, in an acidic solvent (e.g., acetic acid, buffer of pH4.2-7.2 or a mixture of organic solvent (e.g. tetrahydrofuran etc.) and solution thereof etc.), in the presence of zinc powder, sonicated or not sonicated, at a temperature of from 0xc2x0 C. to 40xc2x0 C.
It should be easily understood by those skilled in the art that the carboxyl protecting group of the present invention are not to only t-butylester, benzylester or 2,2,2-trichloroethylester but any group which can be easily and selectively eliminated can be used in the present invention. For example, a protecting group described in Protective Groups in Organic Synthesis (T. W. Greene, Wiley, N.Y. (1991)) may be used. The proposed compounds of the present invention may be easily prepared using those protecting groups and practicing known methods.
For compounds of formula (I) of the present invention, those in which R does not contain a COOH and amino group, AA1 does not contain a COOH and amino group, AA2 does not contain a COOH and amino group, Y does not contain a COOH and amino group and Z or R20 group in Y represent amide group, i.e., the compounds of formula (I-C) 
wherein RC, AA1C, AA2C and YC have the same meaning as hereinbefore defined for R, AA1, AA2 and Y, respectively, provided that all of RC, AA1C, AA2C and YC do not contain a COOH and amino group, and Z or R20 group in YC represent amide group may be prepared by subjecting the amidation, the compound prepared by the same methods (I-B) above and Z or R20 selectively represent xe2x80x94COOH, methylester or ethylester, i.e., the compound of formula (I-B-1) 
wherein YC-B-1 has the same meaning as hereinbefore defined for YC, provided that Z or R20 in Yc represent COOH with an amine compound of formula (III-C-1) 
wherein all the symbols are the same meaning as hereinbefore defined.
Amidation of xe2x80x94COOH group and amine may be carried out by the same method as hereinbefore described.
Amidation of -methylester or ethylester and amine may be carried out, for example, in a water-miscible organic solvent (e.g., methanol, ethanol etc.), an aqueous solution of an amine compound of the formula (III-C-1), at room temperature.
For compounds of formula (I) of the present invention, those in which at least one of R, AA1, AA2 and Y represent contain a COOH and amino group and Z or R20 group in Y represent amide group, may be prepared by subjecting the amino protecting group to elimination hereinbefore described or the carboxy protecting group to elimination hereinbefore described, the compound prepared by the same methods (I-C) above.
A compound of formula (II-a-1) may be prepared by methods known per se. For example, the compound may be produced by methods described in the literature of J. Med. Chem., 37, 563 (1994) or in EP 0623592.
The products of such synthesis reactions may be purified in a conventional manner. For example, it may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
The starting materials and each reagents used in the process for the preparation of the present invention are known per se or may be easily prepared by known methods.
Effect
It has been confirmed that the compounds of formula (I) of the present invention have inhibitory activities on IL-1xcex2 converting enzyme. For example, in laboratory tests the following results were obtained.
Method
(1) Assay for IL-1xcex2 converting enzyme
The reaction mixture contains, for example, 20 mM of HEPES-NaOH pH7.4, 10 mM of KOH, 1.5 mM of MgCl2, 0.1 mM of EDTA and 10% glycerol. Various concentrations of test compounds (50 xcexcl), human ICE solution (50 xcexcl) and various concentrations of substrate (Ac-Tyr-Val-Ala-Asp-MCA) were mixed and incubated at 37xc2x0 C. Fluorescence intensity was measured at En=355 nm and Ex=460 nm. The compounds of the present invention have ICE inhibitory values less than 1 xcexcM (for example, in Example 2(1), the compound has an IC50 of 0.03 xcexcM).
In the aboved example method,
HEPES is 4-(2-Hydroxyethyl)-1-piperazineethane-sulfonic acid,
EDTA is Ethylenediamine tetraacetate, and
Ac-Tyr-Val-Ala-Asp-MCA is Acetyl-L-tyrosyl-L-valyl-L-alanyl-L-asparaginic acid 4-methyl-coumarinyl-7-amide.
Toxicity
The compounds of the present invention are substantially non-toxic. Therefore, the compounds of the present invention may be considered sufficiently safe and suitable for pharmaceutical use.
Application for Pharmaceuticals
Compounds of the present invention have an inhibitory activity on ICE in animals, including humans. Therefore the compounds are useful for prevention and/or treatment of insulin dependent diabetes (type I), multiple sclerosis, acute or delayed type hypersensitivity, infectious diseases, infection complications, septic shock, arthritis, colitis, glomerular nephritis, hepatitis, hepatic cirrhosis, pancreatitis, reperfusion injury, cholangeitis, encephalitis, endocarditis, myocarditis, vasculitis, Alzheimer""s disease, Parkinson""s disease, dementia, cerebral vascular disturbance, neuro-degenerative diseases, bone or cartilage-resorption diseases, AIDS, ARC (AIDS related complex), adult T cell leukemia, hairy cell (pilocytic) leukemia, myelosis, respiratory dysfunction, arthropathy, uveitis, neoplasm, diffuse collagen diseases such as systemic lupus erythematosis or rheumatoid arthritis, ulcerative colitis, Sjogren""s syndrome, primary biliary cirrhosis, idiopathic thrombocytopnic purpura, autoimmonohaemolytic anemia, severe myasthenia, osteodisplasia syndrome, periodic thrombocytopenia, aplastic anemia, idiopathic thrombocytopenia, various diseases accompanied with thrombocytopenia such as disseminated intravascular coagulation, adult dyspnea syndrome, hyperplasia of the prostae gland, myoma of the uterus, asthma bronchiole, arteriosclerosis, various kinds of teratoma, nephritis, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral nervous disturbance, Crohn""s diseases and osteo arthritics etc. essentially disorders arising from or influenced by IL-1xcex2 activity.
For the purpose above described, the compounds of formula (I) of the present invention, non-toxic salts thereof, acid additional salts thereof and hydrates thereof may be normally administered systemically or partially, usually by oral or parenteral administration.
The doses to be administered are determined depending on age, body weight, symptom, the -desired therapeutic effect, the route of administration, the duration of the treatment etc. In the human adult, the dose per person is generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration, up to several times per day, or continuous administration between 1 and 24 hrs. per day intravenously.
As mentioned above, the doses to be used depend on various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention can be administered as solid compositions, liquid compositions or other compositions for oral administration, as injections, liniments or suppositories etc. for parenteral administration.
Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules. Capsules include hard capsules and soft capsules.
In such compositions, one or more of the active compound(s) is or are admixed with at least one inert diluent (such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.). The compositions also may comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents (such as magnesium stearate etc.), disintegrating agents (such as cellulose calcium glycolate etc.), stabilizing agents (such as lactose etc.), and assisting agents for dissolving (such as glutamic acid, asparaginic acid etc.).
The tablets or pills may, if desired, be coated with a film of gastric or enteric material (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate etc.), or be coated with more than two films. Further, the coating may include containment within capsules of absorbable materials such as gelatin.
Liquid compositions for oral administration include pharmaceutically-acceptable solutions, emulsions, suspensions, syrups and elixirs. In such compositions, one or more of the active compound(s) is or are contained in inert diluent(s) commonly used in the art (purified water, ethanol etc.). Besides inert diluents, such compositions also may comprise adjuvants (such as wetting agents, suspending agents etc.), sweetening agents, flavouring agents, perfuming agents and preserving agents.
Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s). Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents (sodium sulfate etc.), isotonic buffer (sodium chloride, sodium citrate, citric acid etc.). For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 (herein incorporated in their entirety by reference) may be used.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. In such compositions, one more of active compound(s) is or are admixed with at least one inert aqueous diluent(s) (distilled water for injection, physiological salt solution etc.) or inert non-aqueous diluent(s) (propylene glycol, polyethylene glycol, olive oil, ethanol, POLYSORBATE80 (registered trade mark) etc.).
Injections may comprise other inert diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent (lactose etc.), assisting agents, such as assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc.
They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile, solid compositions, for example, by freeze-drying, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, and endermic liniments, ointments, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by per se known methods.